General Description

Type 1 diabetes is an autoimmune disease, meaning that the immune system mistakenly attacks the cells in the body that make insulin. These cells, called beta cells, are found in the pancreas. Beta cell destruction starts years before symptoms appear. By the time type 1 diabetes has been diagnosed, many beta cells have already been destroyed, but some are still left.

At this point, there may have some remaining beta cells that can still produce insulin. People who can continue to make a little insulin may have fewer problems with low blood glucose (hypoglycemia). They may also have an easier time keeping their blood glucose at normal levels. This helps lower the risk of long-term complications. At this time, there is no proven treatment that will protect the remaining beta cells. The body's immune system keeps destroying them. Within a few years after diagnosis, most people with type 1 diabetes can no longer make their own insulin.

This is a three-arm, 1:1:1 randomized, placebo controlled, double- blinded trial in which at least 28 subjects will receive active Anti-Thymocyte Globulin and Granulocyte colony-stimulating factor (ATG-GCSF), at least 28 subjects will receive ATG alone and at least 28 subjects will receive placebo alone within 100 days from diagnosis of Type 1 Diabetes (T1D). TrialNet researchers are testing whether ATG used alone or in combination with GCSF will help people continue to make some of their own insulin.

The study has a treatment phase and a follow-up phase. The treatment phase is the first 3 months of the study. During this time, subjects will have one inpatient stay for 3 days and 2 nights to receive two infusions of low dose ATG or placebo followed by one injection (like an insulin injection) of GCSF or placebo. Subjects will return for five additional outpatient visits over the next 10 weeks (every 2 weeks) to receive an injection of GCSF or placebo. After that, subjects will be in the follow-up phase and will return for outpatient visits every 3 to 6 months. Subjects will participate in the study for two years.

Objectives

The primary objective of the study is to determine the safety and ability of low dose ATG plus GCSF and low dose ATG alone to retain/enhance C-peptide production in new onset T1D patients demonstrating residual beta cell function.

The study will also examine the effect of the proposed treatments on surrogate markers for immunologic and metabolic outcomes.

Outcome Measure

Primary Outcome Measure: area under the stimulated C-peptide curve over the first 2 hours of a mixed meal glucose tolerance test conducted at the one-year visit.

The primary statistical hypothesis to be assessed in the study is whether the 2 hour area under the curve (change in baseline to 12 months) in residual beta cell function (C-peptide) will differ between those treated with ATG and GCSF or ATG alone as compared with placebo.

Criteria

Inclusion Criteria:

Subjects between the ages of 12 and 46 years old; with a diagnosis of T1D for less than 100 days at randomization; willing to provide Informed Consent or have a parent or legal guardian provide informed consent if the subject is <18 years of age; positive for at least one islet cell autoantibody; glutamic acid decarboxylase 65 (GAD65A), Insulin micro IAA (mIAA), if obtained within 10 days of the onset of insulin therapy, islet antigen 2 (IA-2A), Islet Cell Antigen (ICA), or zinc transporter 8 (ZnT8A); stimulated C-peptide levels = 0.2 pmol/ml measured during a mixed meal tolerance test (MMTT) conducted at least 21 days from diagnosis of diabetes and within one month (37 days) of randomization; Epstein-Barr virus (EBV PCR) negative within two weeks of randomization if EBV seronegative at screening; at least 6 weeks from last live immunization; able to receive killed influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available; willing to forgo vaccines during the treatment period and for 3 months following last dose of study drug; and willing to comply with intensive diabetes management.

Exclusion Criteria:

Subjects that are immunodeficient or have clinically significant chronic lymphopenia: (Leukopenia (< 3,000 leukocytes /µL), neutropenia (<1,500 neutrophils/µL), lymphopenia (<800 lymphocytes/µL), or thrombocytopenia (<100,000 platelets/µL); have active signs or symptoms of acute infection at the time of randomization; have evidence of prior or current tuberculosis infection as assessed by purified protein derivative (PPD), interferon gamma release assay (IGRA) or by history; currently pregnant or lactating, or anticipate getting pregnant within the two year study period; require use of other immunosuppressive agents including chronic use of systemic steroids; have evidence of current or past human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection; have any complicating medical issues or abnormal clinical laboratory results that may interfere with study conduct, or cause increased risk to include pre-existing cardiac disease, chronic obstructive pulmonary disease (COPD), sickle cell disease, neurological, or blood count abnormalities; have a history of malignancies other than skin; have evidence of liver dysfunction with aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 3 times the upper limits of normal evidence of renal dysfunction with creatinine greater than 1.5 times the upper limit of normal; have a vaccination with a live virus within the last 6 weeks; current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within prior 7 days of screening; active participation in another T1D treatment study in the previous 30 days; prior treatment with abatacept or anti-cd3; known allergy to GCSF or ATG; prior treatment with ATG or known allergy to rabbit derived products; or any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results.

Study Documents

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